The in utero transplantation of hematopoietic stem cells (HSC) has the potential of curing a variety of inherited marrow stem cell defects and inborn errors such as thalassemia, sickle cell anemia, severe immunodeficiency disease and Hurler mucopoly-saccharidosis. The aim of this proposal is to develop a pediatrician with research experience in transplantation into an independent investigator focused on understanding the biology of engraftment and tolerance induction following in utero HSC transplantation. The candidate has established a murine model of in utero HSC transplantation and needs additional training in basic immunology and stem cell biology to carry on in depth studies of stem cell engraftment and tolerance induction. Training and research will be accomplished in 2 phases over a period of 5 years. Phase I (year 1-3) will include didactic courses offered by the Graduate Program in Immunology and Cell Biology at UCSF. It will also involve research on in utero peripheral blood stem cell (PBSC) transplantation in B-thalassemic mice with special emphasis on donor/host kinetics in post-transplant mixed chimeras. Different conditions will be applied using hematopoietic cytokines (Stem Cell Factor, Interleukin-3 and Granulocyte-Colony Stimulating Factor) pre-and postnatally and chemotherapeutic agents (5-FU) to observe differences in proliferation of donor and host cell populations at different levels of progenitor cell differentiation. Donor/host chimerism will be tested at the pluripotent hematopoietic stem cells (PHSC), colony forming units-spleen (CFU-S d 12) and peripheral blood WBC and RBC levels. Phase H (year 4 and 5) will involve in depth studies of tolerance induction following in utero transplantation. The role of permanent donor chimerism in the thymus, central and peripheral clonal deletion and peripheral anergy in tolerance induction will be investigated. Upon completion of the proposed 5 year training and research program the following objectives will have been accomplished: (1) the m-urine model of in utero transplantation in 8-thalassemic mice will be established, (2) the basic mechanisms of tolerance induction following in utero transplanation will be described and (3) future, more in depth studies of tolerance induction will be designed. The candidate will have developed an independent research program involving in utero transplantation and have progressed to a more advanced phase of her academic career.